Although the transdermal drug delivery system, used as non-oral alternative systemic drug delivery system, is a convenient system form for primary and intensive home care (since it does not involve direct injection through the skin), the skin barrier prevents the passage of most drugs. To overcome the skin barrier function temporarily, various physical (iontophoresis, ultrasound, electoporation) and chemical (penetration enhancers, prodrugs) method or their combinations have been used to achieve enhanced transdermal drug transport.1) Among these methods, the most widely used to enhance permeation of stratum corneum barrier are the chemical penetration enhancers.2) Despite the large amount of research and the many different chemical enhancers identified, few have yet reached the market place, because in most of cases, there is a linear correlation between the enhancement effects and skin toxicity.3) This has stimulated research into the combined use of two or more safe and known types of additives. [4][5][6] We have reported a greatly increased effect of l-menthol-ethanol-water (MEW) system on the skin permeation of morphine and several cardiovascular agents compared with their use as single agents. 7,8) The MEW system has a non-selective enhancing effect on a range of both hydrophilic and hydrophobic drugs, and this unselective effect is due to the delipidation of the stratum corneum. This produces skin irritation.9) This result suggests that, if a drug-selective enhancer can be found, it should be possible to minimize the skin irritation. We have found that a lipophilic multicomponent system consisted of L-lactic acid (1%), ethanol (10%) and isopropyl myristate (LEI) system selectively enhances the skin permeation of basic drugs and causes very little skin irritation. [10][11][12] On the other hand, there are many acidic drugs such as NSAIDs which are potentially effective and used routinely in clinical situations. Therefore, it is worthwhile developing a skin permeation enhancer, which would be selective for acidic drugs. In the present study, we have studied a lipophilic multicomponent system consisted of triethanolamine, ethanol and isopropyl myristate (TEI) system, based on our earlier LEI system.
MATERIALS AND METHODS
MaterialsMefenamic acid (MA), monoethanolamine (M), diethanolamine (D), triethanolamine (T) diethylamine (De), triethylamine (Te), propanolamine (P) and aminopyrine, were purchased from Wako Pure Chemical Ind., Ltd. (Osaka, Japan). Ketoprofen was supplied by Nissan Chemical Ind., Ltd. (Tokyo, Japan). Isosorbide dinitrate (ISDN) was supplied by Toko Pharmaceutical Ind. Co., Ltd. (Tokyo, Japan). Ibuprofen and ketotifen fumarate were obtained from Nissei Chemical Co., Ltd. (Tokyo, Japan). Diclofenac sodium, antipyrine and isopropyl myristate (IPM) were obtained from Tokyo Kasei Kogyo Co., Ltd. (Tokyo, Japan). Dehydrated ethanol (E) (JP grade) was purchased from Imazu Yakuhin Kogyo K. K. (Tokyo, Japan). All other chemicals and solvents were of reagent grade.Animals Male hairless rats (WBN/ILA-Ht)...